Non-nucleoside reverse transcriptase inhibitor (NNRTI) cross-resistance: Implications for preclinical evaluation of novel NNRTIs and clinical genotypic resistance testing

摘要

Objectives: The introduction of two new non-nucleoside reverse transcriptase inhibitors (NNRTIs) in the past 5 years and the identification of novel NNRTI-associated mutations have made it necessary to reassess the extent of phenotypic NNRTI cross-resistance. Methods:We analysed a dataset containing 1975, 1967, 519 and 187 genotype-phenotype correlations for nevirapine, efavirenz, etravirineandrilpivirine, respectively. We used linear regression to estimatethe effects of RTmutations on susceptibility to each of these NNRTIs. Results: Sixteen mutations at 10 positions were significantly associated with the greatest contribution to reduced phenotypic susceptibility (≥10-fold) to one or more NNRTIs, including: 14 mutations at six positions for nevirapine (K101P, K103N/S, V106A/M, Y181C/I/V, Y188C/L and G190A/E/Q/S); 10 mutations at six positions for efavirenz (L100I, K101P, K103N, V106M, Y188C/L and G190A/E/Q/S); 5 mutations at four positions for etravirine (K101P, Y181I/V, G190E and F227C); and 6 mutations at five positions for rilpivirine (L100I, K101P, Y181I/V, G190E and F227C). G190E, amutation that causes high-level nevirapine and efavirenz resistance, also markedly reduced susceptibility to etravirineand rilpivirine. K101H, E138G, V179FandM230Lmutations, associated with reduced susceptibility to etravirine and rilpivirine, were also associated with reduced susceptibility to nevirapine and/or efavirenz. Conclusions: The identification of novel cross-resistance patternsamong approved NNRTIs illustrates the need fora systematic approach for testing novel NNRTIs against clinical virus isolates with major NNRTI-resistancemutations and for testing older NNRTIs against virus isolates withmutations identified during the evaluation of a novel NNRTI.